Molecular cytogenetics has had a major impact on chromosome analysis in both research and clinical laboratories. Telomeres, together with the centromere, define the physical limits of each chromosome. Chromosome-specific centromere probes are presently available. These probes, in conjunction with chromosome-specific telomere probes, would allow detection of all major translocations involving a telomere as well as submicroscopic translocations which are strongly indicated as a frequent cause of mental retardation, infertility and miscarriage, and specific human cancers and leukemias. The Phase I proposal addresses the feasibility of developing chromosome- specific telomeric probes utilizing a sophisticated strategy libraries to isolate clones for building sets of overlapping cosmids (contigs) to use as molecular probes. Teleomeres on the short arms of chromosome 1 (1p) , 4 (4p), and 17 (17p) are targeted for Phase I. Developed probes will be evaluated on a variety of clinical samples. Multiple color analysis for simultaneous detection of multiple probes will be investigated. Completion of Phase I will yield clinically-significant in situ probes for human telomeres and establish a methodology that will greatly enhance all levels of molecular probe development.